Condensed azepines as vasopressin agonists

ABSTRACT

This invention provides novel compounds according to general formula (1) wherein A is a bicyclic or tricyclic azepine derivative, V 1  and V 2  are both H, OMe or F, or one of V 1  and V 2  is Br, Cl, F, OH, OMe, OBn, OPh, O-acyl, N 3 , NH 2 , NHBn or NH-acyl and the other is H, or V 1  and V 2  together are ═O, —O(CH 2 ) p O— or —S(CH 2 ) p S—; W 1  is either O or S; X 1  and X 2  are both H, or together are ═O or ═S; Y is OR 5  or NR 6 R 7 ; R 1 , R 2 , R 3  and R 4  are independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br; R 5  is selected from H and lower alkyl; R 6  and R 7  are independently selected from H and lower alkyl, or together are —(CH 2 ) n ; n=3, 4, 5, 6; and p is 2 or 3. The compounds are agonists at the vasopressin V2 receptor and are useful as antidiuretics and procoagulants. The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.

FIELD OF INVENTION

[0001] The present invention relates to a class of novel chemicalentities which act as agonists of the peptide hormone vasopressin. Theyreduce urine output from the kidneys and so are useful in the treatmentof certain human diseases characterised by polyuria. They are alsouseful in the control of urinary incontinence and bleeding disorders.

BACKGROUND TO THE INVENTION

[0002] Vasopressin is a peptide hormone secreted by the posteriorpituitary gland. It acts on the kidney to increase water retention andso reduce urine output. For this reason, vasopressin is alternativelyknown as “antidiuretic hormone”. It also acts on the vasculature, whereit produces a hypertensive effect. The cellular receptors that mediatethese two actions have been characterised and shown to be different. Theantidiuretic action is mediated by the type-2 vasopressin receptor,commonly called the V₂ receptor. Agents that can interact with the V₂receptor and activate it in the same way as vasopressin are called V₂receptor agonists (or simply V₂ agonists). Such agents will have anantidiuretic action. If these agents interact selectively with the V₂receptor and not the other vasopressin receptor subtypes, then they willnot have the hypertensive effect of vasopressin. This would be animportant safety consideration and make such agents attractive for thetreatment of human disease conditions characterised by polyuria (whichis herein taken to mean excessive urine production).

[0003] In fact, such an agent is already in use in human therapy.Desmopressin (otherwise [1-desamino, D-Arg⁸]vasopressin, Minirin™,DDAVP™) is a peptide analogue of vasopressin which is selectively anagonist at the V₂ receptor. It is used in the treatment of centraldiabetes insipidus, which is a condition that results from defectivesecretion of vasopressin. It is also employed in the control ofnocturnal enuresis and may also be of use in the control of nocturia.However, desmopressin is not an ideal agent in all respects. Even thebest current syntheses of the agent are lengthy, and desmopressin is notamenable to the most convenient of purificaton techniques such ascrystallisation. Consequently, desmopressin is relatively expensive. Ithas a very low oral bioavailability, and there is some variability inthis parameter.

[0004] Overall then, there exists a need for a selective vasopressin V₂receptor agonist that is easy to prepare and purify, and that has a highand predictable oral bioavailability. Such properties are most likely tobe obtained with a non-peptide compound. These considerations have ledother groups to investigate non-peptide vasopressin V₂ agonists, andtheir results are disclosed in, for example, International PatentApplications WO97/22591, WO99/06403, WO99/06409, WO00/46224, WO00/46225,W00/46227 and WO00/46228. The compounds disclosed in these documentsare, however, less than ideal. In particular, they have poor oralbioavailability, probably due in part to their low aqueous solubility.The present invention provides compounds with improved solubility andbloavailability.

[0005] Besides its antidiuretic actions, desmopressin is used toincrease the concentration in the blood of the coagulation proteinsknown as Factor VIII and von Willebrand factor. In the clinical context,this makes desmopressin useful in the treatment of haemophilia A and vonWillebrand's disease. Similar applications would be open to thenon-peptide agonists of the present invention.

SUMMARY OF THE INVENTION

[0006] As disclosed herein, the present invention relates to a series ofcompounds that are non-peptide agonists of vasopressin and which areselective for the V₂ receptor subtype. The compounds are described bygeneral formula 1

[0007] wherein:

[0008] A is a bicyclic or tricyclic azepine derivative selected fromgeneral formulae 2 to 7

[0009] A¹, A⁴, A⁷ and A¹⁰ are each independently selected from CH₂, Oand NR⁸;

[0010] A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A15 are each independently selectedfrom CH and N;

[0011] either A⁵ is a covalent bond and A⁶ is S, or A⁵ is N═CH and A⁶ isa covalent bond;

[0012] A⁸ and A¹² are each independently selected from NH and S;

[0013] A¹⁶ and A¹⁷ are both CH₂, or one of A¹⁶ and A¹⁷ is CH₂ and theother is selected from O, SO_(x), and NR⁸,

[0014] V¹ and V² are both H, OMe or F, or one of V¹ and V² is Br, Cl, F,OH, OMe, OBn, OPh, O-acyl, N₃, NH₂, NHBn or NH-acyl and the other is H,or V¹ and V² together are ═O, —O(CH₂)_(p)O— or —S(CH₂)_(p)S—;

[0015] W¹ is either O or S;

[0016] X¹ and X² are both H, or together are ═O or ═S;

[0017] Y is OR⁵ or NR⁶R⁷;

[0018] Z is S or —CH═CH—;

[0019] R¹, R², R³ and R⁴ are independently selected from H, lower alkyl,lower alkyloxy, F, Cl and Br;

[0020] R⁵ is selected from H and lower alkyl;

[0021] R⁶ and R⁷ are independently selected from H and lower alkyl, ortogether are —(CH₂)_(n)—;

[0022] R⁸ is H or lower alkyl;

[0023] n=3, 4, 5or6;

[0024] p is 2 or 3; and

[0025] x is 0, 1 or2.

[0026] The invention further comprises pharmaceutical compositionsincorporating these vasopressin agonists, which compositions areparticularly useful in the treatment of central diabetes insipidus,nocturnal enuresis and nocturia.

DESCRIPTION OF THE INVENTION

[0027] The present invention comprises N-benzylcarbamyl pyrrolidinederivatives defined by general formula 1.

[0028] In this formula, A represents a bicyclic or tricyclic azepinegroup according to one of the general formulae 2-7.

[0029] A¹, A⁴, A⁷ and A¹⁰ represent divalent groups selected frommethylene (—CH₂—), oxygen (—O—) and substituted nitrogen (—NR⁸—). A²,A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ represent either a nitrogen atom (—N═) ora methine group (—CH═). A⁵ can represent a covalent bond, in which caseA⁶ represents a sulphur atom (—S—) such that the ring that includesthese two groups is a thiophene ring. Alternatively, A⁵ can represent agroup —N═CH—, in which case A⁶ represents a covalent bond such that thering that includes these two groups is a pyridine ring. A⁸ and A¹²represent either —NH— or a sulphur atom (—S—). A¹⁶ and A¹⁷ representdivalent groups. Both may be methylene groups (—CH₂—) or one is amethylene group and the other is selected from hydroxymethylene(—CH(OH)—), difluoromethylene (—CF₂—), oxygen (—O—), substitutednitrogen (—NR⁶—) and sulphur or oxidised sulphur (—S—, —SO—, or —SO₂—).V¹ and V² may both be hydrogen, methoxy or fluorine, or one may beselected from bromine, chlorine, fluorine, hydroxy, lower alkoxy,benzyloxy, phenoxy, acyloxy, azido, amino, benzylamino and acylamido(Br, Cl, F, OH, O-lower alkyl, OBn, OPh, O-acyl, NH₂, NHBn and NH-acyl)provided that the other is hydrogen, or V¹ and V² together may representan oxygen atom such that the fragment CV¹V² is a carbonyl group (C═O).V¹ and V² may also be an ethylene- or propylene-dioxy or -dithio chain(—O(CH₂)₂O—, —O(CH₂)₃O—, —S(CH₂)₂S—, —S(CH₂)₃S—) such that CV¹V² is a1,3-dioxolane, 1,3-dioxane, 1,3-dithio 1,3 dithiane ring.

[0030] W¹ is either an oxygen or a sulphur atom.

[0031] X¹ and X² may either both be hydrogen, or together they mayrepresent an oxygen or sulphur atom such that the fragment CX¹X² is acarbonyl or thiocarbonyl group (C═O or C═S).

[0032] Y is either a group —OR⁵ or a group —NR⁶R⁷.

[0033] Z represents either a sulphur atom, such that the ring thatincludes it is a thiophene ring, or it represents a group —CH═CH—, suchthat the ring is a benzene ring.

[0034] R¹, R², R³ and R⁴ are each independently selected from hydrogen,lower alkyl groups, lower alkyloxy groups and the halogens fluorine,chlorine and bromine.

[0035] R⁵ may be either a hydrogen atom or a lower alkyl group.

[0036] R⁶ and R⁷ may each independently be hydrogen atoms or lower alkylgroups, or together they may constitute a chain of between 3 and 6methylene groups such that, together with the nitrogen atom to whichthey are attached, they form an azetidine, pyrrolidine, piperidine orperhydroazepine ring.

[0037] R⁸ may be hydrogen or a lower alkyl group.

[0038] In the context of the present disclosure, the term “lower alkyl”is intended to include straight chain and branched alkyl groups andcycloalkyl groups of between 1 and 6 carbon atoms. For example, methyl,ethyl, isopropyl, tert-butyl, neopentyl and cyclohexyl are all withinthe scope of the term lower alkyl. The term “acyl” denotes lower alkylcarbonyl groups such as acetyl, pivaloyl, cyclopropylcarbonyl and thelike. Formyl is also considered to be an acyl group.

[0039] Certain compounds of general formula 1 are capable of formingsalts with acids or bases. For example, compounds containing one or morenitrogen atoms can form addition salts with mineral and organic acidssuch as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,trifluoroacetic add, methanesulphonic acid, citric acid and benzoicacid. Compounds containing acidic groups can form salts with bases.Examples of such salts include the sodium, potassium, calcium,triethylammonium and tetraethylammonium salts. Furthermore, compoundsthat have both acidic and basic groups can form internal salts(zwiterions). Insofar as these salts are pharmaceutically acceptable,they are included within the scope of the invention.

[0040] The compounds according to general formula 1 all have at leastone stereogenic centre (a tetrahedral carbon atom bearing four differentsubstituents) and so can exist as optical isomers such as enantiomersand diastereomers. Such isomers, and mixtures thereof, are all intendedto be within the scope of the present invention.

[0041] In a preferred embodiment of the present invention, A is a groupaccording to general formula 2. In another preferred embodiment of thepresent invention, A is a group according to general formula 3. Inanother preferred embodiment of the present invention, A is a groupaccording to general formula 4. In another preferred embodiment of thepresent invention, A is a group according to general formula 5. Inanother preferred embodiment of the present invention, A is a groupaccording to general formula 6.

[0042] In another preferred embodiment of the present invention, A is agroup according to general formula 7. In a more preferred embodiment, Ais a tetrahydro-1-benzazepin-1-yl group, i.e. a group according togeneral formula 7 in which Z is —CH═CH— and both A¹⁶ and A¹⁷ aremethylene groups.

[0043] In another preferred embodiment, one of R¹ and R² is chlorine ora methyl group and the other is hydrogen, with both R³ and R⁴ also beinghydrogen.

[0044] In another preferred embodiment, one of V¹ and V² is a methoxy orbenzyloxy group and the other is hydrogen.

[0045] In yet another preferred embodiment, X¹ and X² together representan oxygen atom and Y is —NR⁶R^(7.)

[0046] Particularly preferred embodiments of the present invention arethose that combine two or more of the above preferred features.

[0047] A still more preferred embodiment of the present invention is acompound according to general formula 8.

[0048] In general formula 8, W¹, R⁵ and R⁶ are as defined above for 1.One of R^(a) and R_(b) is hydrogen and the other is either chlorine or amethyl group. R^(c) is either a methyl group or a benzyl group.

[0049] A yet more preferred embodiment is a compound of general formula8A in which the stereochemistry is as shown.

[0050] Another preferred embodiment of the present invention is acompound according to general formula 1 in which V¹ and V² are bothhydrogen. In a more preferred embodiment, X¹ and X² together are anoxygen atom and Y is NR⁶R⁷. More preferred still is a compound accordingto general formula 9.

[0051] In general formula 9, W¹, R⁵ and R⁶ are as defined above for 1.One of R^(a) and R^(b) is hydrogen and the other is either chlorine or amethyl group.

[0052] Even more preferred is a compound according to general formula 9Ain which the stereochemistry is as shown.

[0053] Individual preferred compounds within the present inventioninclude (but are not limited to) the following:

[0054]1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,

[0055](4R)-4hydroxy-1-(2-methyl-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,

[0056](4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)4-methoxy-L-proline-N,N-dimethylamide,

[0057](4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,

[0058](4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,

[0059](4R)4methoxy-1-(2-methyl-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,

[0060](4R)-4-methoxy-1-(3-methyl4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,

[0061](4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro4H-thieno[3,2-b]azepin4-ylcarbonyl)benzyl-carbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,

[0062] (4R)-1-(4-(10,11 -dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10ylcarbonyl)-2-methyl-benzylcarbamoyl)-4methoxy-L-proline-N,N-dimethylamide,

[0063] (4R)-1-(2-chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-benzylcarbamoyl)4-methoxy-L-proline-N,N-dimethylamide,and

[0064](4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylthioamide.

[0065] The compounds of the present invention can be prepared usingmethods generally known in the art. The compounds of general formula 1can be considered to be composed of three linked fragments (A-C).

[0066] The three fragments will generally be prepared separately andthen combined at a late stage in the synthesis. Some instances of thevarious groups (R¹-R⁴, V¹, V², X¹, X² etc.) might be incompatible withthis assembly and so will require the use of protecting groups. The useof protecting groups is well known in the art (see for example“Protective Groups in Organic Synthesis”, T. W. Greene,Wiley-Interscience, 1981). Particular groups that may require protectionare amines (protected as amides or carbamates), alcohols (protected asesters or ethers) and carboxylic acids (protected as esters). For thepurposes of this discussion, it will be assumed that such protectinggroups as are necessary are in place.

[0067] The fragments A, B and C can be combined according to twostrategies to give the compounds of formula 1. In the first, fragments Aand B are linked to give a fragment corresponding to AB, which is thencombined with fragment C. In the second, fragments B and C are linked togive a fragment corresponding to BC, which is then combined withfragment A. The chemistry involved in the condensation of fragment Awith B, and that involved in the condensation of fragment B withfragment C, will be the same whichever strategy is followed. We havefound that the first strategy is more flexible when working on a smallscale and for preparing a selection of compounds. Nevertheless, it ispossible that the second strategy would be advantageous for thepreparation of a selected compound on a large scale.

Formation of Fragment AB

[0068]

[0069] Here, {A} and {B} represent part structures of the fragments Aand B respectively. The formation of amides by the condensation ofcarboxylic acids with amines is well known. In general, the acid and theamine are mixed in an aprotic solvent such as dichloromethane ordimethylformamide in the presence of a condensing agent such as acarbodiimide (for example “water-soluble carbodiimide”, which isN-ethyl-N-(3-dimethylaminopropyl)-carbodiimide) or a reactive phosphorusderivative (for example “BOP”, which is(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate). The reaction may optionally be catalysed by atertiary amine such as triethylamine or 4-dimethylaminopyridine.Alternatively, the carboxylic acid may be converted to a more reactivederivative such as the acid chloride. Such a derivative can then bereacted with the amine as described above but without the need for acondensing agent.

Formation of Fragment BC

[0070]

[0071] Formation of the urea or thiourea bond between fragments B and Ccan be most easily achieved by allowing the primary amine correspondingto fragment B to react with a derivative of carbonic acid such asphogene (wherein LG above is chlorine) or carbonyidiimidazole (whereinLG is 1-imidazolyl) to form an intermediate carbamic acid derivative.When W¹ is sulphur rather than oxygen, thiophosgene orthiocarbonyldiimidazole is used. The reaction is conveniently carriedout in an aprotic solvent such as dichloromethane or dimethylformamidein the presence of a tertiary amine such as triethylamine orN,N-diisopropylethylamine. After allowing sufficient time for theformation of the intermediate, the secondary amine corresponding tofragment C can be added to the reaction mixture. It is not necessary toisolate the intermediate carbamate derivative.

[0072] As a variation of this process, it is possible to reverse theorder of addition of the amines corresponding to fragments B and C, suchthat the carbamate derivative is formed from the secondary amine, andthe primary amine is added subsequently.

[0073] Overall then, the following intermediates are required for thesynthesis of the compounds of the present invention

[0074] i) For Fragment A

[0075] Fused azepines according to these general formulae can beprepared according to methods reported in the literature. See forexample: Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Articoet al., Farmaco. Ed. Sci. 24, 1969, 276; Artico et al., Farmaco. Ed.Sci. 32, 1977, 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878;Chakrabarti at al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J.Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601;Grunewald et al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med.Chem. 35, 1992, 1887; Liegéois et al., J. Med. Chem. 37, 1994, 519;Olagbemiro et al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med.Chem. 23, 1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; andInternational patent application, publication number WO99106403.

[0076] Some of them are Items of commerce.

[0077] ii) For Fragment B

[0078] Because the primary amine and the carboxylic acid groups areincompatible, they must be developed separately and protected.Substituted benzoic acids are well known, and the carboxylic acid isconveniently protected as its methyl ester. The primary amine can beelaborated from the corresponding nitrile (by reduction) or the alcohol(by displacement with a nitrogen nucleophile). The best method willdepend on the nature of the substituents R¹-R⁴.

[0079] iii) For Fragment C

[0080] Pyrrolidine derivatives of this type are prepared according tothe methods described in the literature. See for example: Dugave et al.,Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31, 1988,1148; and Smith et al., J. Med. Chem. 31, 1988, 875.

[0081] Proline and hydroxyproline derivatives of defined stereochemistryare items of commerce and as such are convenient starting materials.

[0082] The present invention further comprises pharmaceuticalcompositions that include at least one compound according to theforegoing description as an active constituent. The composition may alsoinclude a second pharmacological agent such as a spasmolytic or apotassium channel blocker, these agents being known in the art toameliorate bladder dysfunction. Preferably, the composition includesonly one active constituent. The composition will include excipientsselected from binding agents, bulking agents, dispersants, solvents,stabilising agents and the like, such excipients being generally knownin the art.

[0083] The excipients used will depend on the intended nature of theformulation, which will, in turn, depend on the intended route ofadministration. Administration may be oral, transmucosal (such assublingual, buccal, intranasal, vaginal and rectal), transdermal or byinjection (such as subcutaneous, intramuscular and intravenous). Oraladministration is generally preferred. For oral administration, theformulation will be a tablet or capsule. Other formulations include drypowders, solutions, suspensions, suppositories and the like.

[0084] In a further aspect, the present invention is a method oftreating or controlling certain human physiological dysfunctions. Thismethod comprises the administration to the person in need of suchtreatment of an effective amount of a pharmaceutical composition, whichcomposition contains a compound according to the foregoing descriptionas an active constituent. The compounds act to reduce urine output, andso the method of the invention can be applied to all conditions in whichelevated urine output is a contributory factor. The compounds alsoincrease the production of the blood coagulation proteins known asFactor VIII and von Willebrand factor, and so the treatment of bleedingdisorders can be undertaken.

[0085] In a preferred embodiment, the condition treated is diabetesinsipidus. This is a condition caused by an inability of the body toproduce and secrete physiologically active vasopressin, with the resultthat water re-uptake is greatly reduced and large volumes of urine areproduced.

[0086] In another preferred embodiment, the condition treated isnocturnal enuresis. This is defined as bladder emptying while theindividual is sleeping. It is a condition that mainly affects childrenand a number of factors may be involved in its etiology.

[0087] In another preferred embodiment, the condition treated isnocturia. This is defined as production of sufficient urine during thenight to require the individual to wake and empty his (or her) bladder.Again, this condition may be the result of a number of factors.

[0088] In another preferred embodiment, the condition treated isincontinence. This condition is characterised, in part, by reducedbladder capacity and control such that involuntary urination occursunless the bladder is emptied frequently. Incontinence has been dividedinto two conditions, stress incontinence and urge incontinence. A numberof etiological factors are thought to be involved. Treatment accordingto the invention is particularly useful for delaying the need forbladder emptying (“voiding postponement”) in order to allow theincontinent subject a dry period of a few hours (such as up to fourhours). Such voiding postponement may also be useful for thenon-incontinent population, for example for people obliged to remain inmeetings for extended periods.

[0089] In another preferred embodiment, the condition treated ishaemophilia A or von Willebrand's disease. These are conditions in whichFactor VIII or von Willebrand factor production is reduced and theindividual suffers from prolonged bleeding.

[0090] In another preferred embodiment, the composition is administeredprior to surgery (including dental surgery) to increase thecoagulability of the blood and so reduce peri-operative blood loss.

[0091] The administration of the compositions of the present inventionwill generally be under the control of a physician. The physician willdetermine the amount of composition to be administered and the dosingschedule, taking into account the patient's physical condition and thetherapeutic goals. For an adult diabetes insipidus patient, a typicaldose might be between 50 mg and 1 g of the active compound per day,taken as a single tablet or as up to four tablets throughout the day.For routes of administration other than the oral route, the amount ofcompound will be reduced, since non-oral routes tend to be moreefficient in terms of delivering therapeutic agents into the systemiccirculation. For the treatment of haemophilia A and von Willebrand'sdisease the amount of compound may need to be higher than for thetreatment of diabetes insipidus.

[0092] The foregoing general description will now be further illustratedwith a number of non-limiting examples.

EXAMPLES Abbreviations

[0093] The following abbreviations have been used. Ac Acetyl AIBNAzo-bis-(isobutyronitrile) Bn Benzyl BOC tert-Butyloxycarbonyl (BOC)₂ODi-tert-butyl dicarbonate DMF Dimethylformamide Et Ethyl EtOAc Ethylacetate IPA Isopropanol iPr Isopropyl M.S. Mass spectrometry Me MethylNBS N-Bromosuccinimide pet. ether petroleum ether, fraction boiling at60-80° C. Ph Phenyl tBu tert-Butyl THF Tetrahydrofuran WSCDIWater-soluble carbodiimide

Preparation of Intermediates

[0094] Reagents corresponding to fragment A and C were commerciallyavailable or prepared according to the published procedures except wheredetailed in the specific Examples. Reagents corresponding to fragment Bwere prepared as detailed below.

EXAMPLE A 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

[0095]

A1. Methyl 4bromomethyl-3-chlorobenzoate

[0096] To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol)and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18h. The mixture was allowed to cool to room temperature and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).

A2. 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

[0097] To a saturated solution of ammonia in ethanol (170 ml) was addedmethyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9mmol). The mixture was stirred at room temperature for 1 h and thenconcentrated in vacuo. The residue was triturated with diethyl ether andthe resultant white crystals were filtered off and washed with morediethyl ether. To a solution of this solid in water (100 ml) were addedsolutions of (BOC)₂O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodiumhydroxide (1.86 g, 46.0 mmol) in water (100 ml). The mixture was stirredat room temperature for 18 h and then concentrated in vacuo. The aqueousresidue was acidified with citric acid and extracted withchloroform/IPA. The organic layer was washed with water, dried overMgSO₄, and concentrated in vacuo to give a white solid; yield 2.89(67%).

EXAMPLE B 4-Cyano-3-methylbenzoic acid

[0098]

[0099] To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol)in THF (100 ml) at −78° C. under a nitrogen atmosphere was addeddropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). Themixture was stirred at −78° C. for 1 h and then poured onto solid carbondioxide (5 g) in THF (50 ml). The mixture was allowed to warm to roomtemperature. Water was added (200 ml) and the mixture was extracted withdiethyl ether (3 times). The aqueous layer was acidified by addition ofconcentrated HCl and extracted with chloroform (3 times). The combinedchloroform extracts were washed with water, dried over MgSO₄, andconcentrated in vacuo to give a white solid; yield 1.2 g (73%).

EXAMPLE C 4-Cyano-2-methylbenzoic acid

[0100]

[0101] 4-Bromo3-methylbenzonitrile (2.0 g, 10.2 mmol) was reactedfollowing the method of Example B to give a yellow solid which wastriturated with hexane and filtered off; yield 0.96 g (59%).

[0102] Reagents corresponding to fragments A, B and C were combined togive the specific Examples as detailed below.

EXAMPLE 11-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-I-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

[0103]

1A.2-Methyl-4-((2,3,4,5-tetrahydro-1H-benzo[b]azepine)-1-carbonyl)-benzonitrile

[0104] To a solution of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.80 g,5.44 mmol) in dichloromethane (50 ml) were added 4cyano-3methylbenzoicacid (0.96 g, 5.95 mmol), triethylamine (0.60 g, 5.95 mmol),4(dimethylamino)pyridine (0.73 g, 5.95 mmol) and WSCDI (1.24 g, 6.48mmol). The mixture was stirred at reflux for 18 h, cooled and evaporatedin vacua. The residue was partitioned between EtOAc and 1M KHSO₄. Theorganic layer was washed with saturated sodium bicarbonate solution andbrine, dried over MgSO₄, and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica (eluant EtOAc:pet. ether30:70); yield 1.10 g (70%).

1B.1-(4-(Aminomethyl)-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepinehydrochloride

[0105] To a degassed solution of the cyanobenzazepine of Example 1A(1.10 g, 3.79 mmol) in methanol (50 ml) were added concentratedhydrochloric acid (0.98 ml, 11.3 mmol) and 10% palladium on carbon (0.80g). Hydrogen gas was bubbled through the mixture for 5 h at roomtemperature. The catalyst was removed by filtering through a pad ofcelite and the filtrate was evaporated; yield 1.23 g (98%).

1C.1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl-L-proline-N,N-dimethylamide

[0106] To a solution of the amine of Example 1B (0.10 g, 0.302 mmol) inDMF (10 ml), under a nitrogen atmosphere, were addedN,N-diisopropylethylamine (43 mg, 0.332 mmol) and carbonyl diimidazole(0.074 g, 0.453 mmol). The mixture was stirred at room temperature for40 minutes. A solution of proline-N,N-dimethylamide (0.107 g, 0.756mmol) in DMF (1 ml) was added. The mixture was stirred at roomtemperature for a further 16 hr. The solvent was removed in vacuo andthe crude material was purified by flash chromatography on silica(eluant methanol:dichloromethane 5:95); yield 0.115 g (82%).

[0107]¹H NMR (CDCl₃): δ1.35-1.55 (1H, m), 1.74-2.10 (3H, m), 2.11 (3H,s), 2.17-2.35 (1H, m), 2.60-2.82 (2H, m), 2.86 (3H, s), 2.90-3.14 (2H,m), 3.05 (3H, s), 3.26 (1H, dd, J−14.9 & 7.2 Hz), 3.40-3.53 (1H, m),3.64-3.84 (1H, m), 4.03-4.19 (1H, m), 4.29-4.42 (1H, m), 4.55-4.68 (1H,m), 4.74-4.81 (1H, m), 4.85-4.98 (1H, m), 6.58 (1H, d, J=7.7 Hz),6.75-6.89 (2H, m), 6.91-7.06 (3H, m), 7.16 (1H, d, J=6.5 Hz), 7.93-8.03(1H, m) ppm.

[0108] M.S.: calc m/e=462.26; found [M+H]⁺=463.2

EXAMPLE 2(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0109]

2A. L-trans4Hydroxyproline-N,N-dimethylamide hydrochloride

[0110] To a solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) indichloromethane (100 ml) were added N,N-diisopropylethylamine (3.7 ml,21.24 mmol), 4-(dimethylamino)pyridine (1.74 g, 14.24 mmol),dimethylamine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g,16.68 mmol). The mixture was stirred at room temperature for 30 hr. Themixture was diluted with dichloromethane (100 ml) and washed with 0.3MKHSO₄, saturated sodium bicarbonate solution and brine, dried overMgSO₄, and concentrated in vacuo to give a colourless gum. This crudematerial was taken up in 4N HCl/dioxan (50 ml) and stirred at roomtemperature for 1 hr and then concentrated in vacua. The residue wasazeotroped with toluene and diethyl ether to give a white solid; yield0.45 g (17%).

2B.(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0111] The amine of Example 1B (0.10 g, 0.302 mmol) was reacted with theamine of Example 2A (0.153 mg, 0.785 mmol) following the method ofExample 1C. The product was purified by flash chromatography on silica(eluant chloroform:methanol:acetic acid 95:4:1); yield 0.95 g (66%).

[0112]¹H NMR (CDCl₃): δ1.65-1.80 (2H, m), 1.85-2.00 (3H, m), 2.05-2.25(1H, m), 2.10 (3H, s), 2.80-3.10 (3H, m), 2.85 (3H, s), 3.00 (3H, s),3.40-3.30 (1H, m), 3.45-3.55 (1H, m), 3.65-3.95 (1H, m), 4.00-4.10 (1H,m), 4.30-4.55 (1H, m), 4.91 (1H, t, J=7.7 Hz), 5.15-5.30 (1H, m)6.10-6.20 (1H, m), 6.55-6.65 (1H, m), 6.85-7.50 (5H, m) ppm.

[0113] M.S.: calc m/e=478.26; found [M+H]⁺=479.2

EXAMPLES 3-116

[0114] The additional examples set out in the following Tables wereprepared using analogous methods.

Example No R/S V² X Y [M + H]⁺ 3 S H H₂ OMe 436.4 4 R H H₂ OMe 436.2 5R/S OPh O OH 528.3 6 R/S OPh O NMe₂ 555.3

Example No R¹ R² V¹ V² X Y [M + H]⁺ 7 H Me H H O OtBu 492.5 8 H Me H H OOH 436.3 9 H Me H OH O OMe 466.0 10 H Me H OAc O NMe₂ 521.0 11 H Me ═O ONMe₂ 477.3 12 H Me H OH O OEt 480.2 13 H Me H OCOcC₃H₅ O NMe₂ 547.3 14 HMe H OMe O NMe₂ 493.5 15 H Cl H H O NMe₂ 483.4 16 H Me H H S NMe₂ 479.217 H Me H H O NMeEt 477.2 18 H OMe H H O NMe₂ 479.2 19 H Me H OMe O OMe480.2 20 H Me H H O OiPr 478.2 21 H Me H OH O OH 452.1 22 H Me H OBn OOiPr 584.2 23 H Me H OH O OiPr 494.1 24 H Me H OBn O NMe₂ 569.2 25 Me HH H O NMe₂ 463.2 26 H Me H OMe O OH 466.2 27 Cl H H H O NMe₂ 483.1 28 HEt H H O NMe₂ 477.3 29 H Cl H H S NMe₂ 499.2 30 H Cl H OBn O NMe₂ 589.231 H Cl H OH O NMe₂ 499.2 32 H Me H OEt O NMe₂ 507.3 33 H Me Br H O NMe₂541.1 34 H Me H Cl O OMe 484.1 35 H Me F F O NMe₂ 499.2 36 H Me H Cl OOH 470.1 37 H Me H N₃ O NMe₂ 504.3 38 H Me H Cl O NMe₂ 497.2 39 H Me HOtBu O NMe₂ 535.3 40 H Me Cl H O NMe₂ 497.2 41 H Me H OPh O OMe 542.3 42H Me H F O OMe 468.3 43 H Me H F O OH 454.4 44 H Me H F O NMe₂ 481.3 45H Me H NHBn O NMe₂ 568.0 46 H Me OMe OMe O OMe 510.3 47 H Me OMe OMe OOH 496.2 48 H Me OMe OMe O NMe₂ 523.3

Example No R² V² X [M + H]⁺ 49 Cl H O 489.1 50 Me H O 469.2 51 Me OH O485.0 52 Cl OMe O 519.3 53 Me OMe O 499.3 54 Cl OMe S 535.1

Example No R³ V² W¹ X [M + H]⁺ 55 H H S O 479.4 56 H OH S O 495.0 57 H HS S 495.1 58 Me H O O 477.2 59 H OBn S O 585.2 60 H OBn O S 585.0

Example No A¹⁶ A¹⁷ R² V² [M + H]⁺ 61 NEt CH₂ Me OMe 522.4 62 NH CH₂ MeOMe 494.3 63 CH₂ NiPr Me OMe 536.4 64 CH₂ NH Me OMe 494.5 65 O CH₂ ClOMe 515.2 66 CH(OH) CH₂ Me H 479.2

Example No A V² [M + H]⁺ 67

H 518.0 68

H 532.2 69

H 527.0 70

H 516.1 71

H 515.0 72

H 514.6 73

H 513.7 74

H 502.1 75

H 500.7 76

OH 547.9 77

OH 517.6 78

OH 546.3 79

H 517.2 80

OBn 619.2 81

OMe 543.4 82

OMe 544.3 83

OMe 549.2 84

OMe 548.2 85

OMe 562.1 86

OMe 590.2

Example No V¹ V² X Y [M + H]⁺ 87 H H S NMe₂ 516.2 88 H OBn O NMe₂ 606.389 H OH O NMe₂ 507.3 90 H OMe O NMe₂ 530.3 91 —OCH₂CH₂O— O OMe 545.3 92OMe OMe O OMe 547.3 93 —OCH₂CH₂O— O NMe₂ 558.3 94 —SCH₂CH₂S— O NMe₂590.2

Example No R² V¹ V² X Y [M + H]⁺ 95 Me H OH O NMe₂ 516.1 96 Me H H SNMe₂ 516.2 97 Me H OMe O NMe₂ 530.4 98 Me —OCH₂CH₂O— O OMe 545.3 99 Me—OCH₂CH₂O— O OH 531.3 100 Me —OCH₂CH₂O— O NMe₂ 558.3 101 Cl H H O NMe₂551.5 102 Me H OMe O NEt₂ 558.3 103 Me H OMe O

570.3 104 Me H OMe S NMe₂ 546.2

Example No A¹⁰ R² V² X [M + H]⁺ 105 O Me H O 519.3 106 NMe Me H O 532.3107 NMe Me OH O 548.1 108 NMe Me OBn O 638.2 109 NMe Me OMe O 562.3 110O Me OMe O 549.2 111 NMe Me Cl O 566.2 112 NMe Me OMe S 578.2 113 O ClOMe O 569.1 114 O Me OMe S 565.2 115 O Cl OMe S 585.1 116 NH Me OMe O548.2

EXAMPLE 117 In Vitro Biological Characterisation

[0115] The compounds of the invention are selective agonists at the V₂receptor. In standard radio-ligand displacement assays, the compoundsall give K₁ values below 10 μM for the V₂ receptor.

EXAMPLE 118 In Vivo Biological Characterisation

[0116] The Brattleboro rat is recognised model for vasopressindeficiency (for a review see FD Grant, “Genetic models of vasopressindeficiency”, Exp. Physiol. 85, 203S-209S, 2000). The animals do notsecrete vasopressin and consequently produce large volumes of diluteurine. Compunds of the invention were administered to Brattleboro rats(0.1-10 mg/kg p.o. in methylcellulose. Urine was collected hourly andvolumes were compared with control animals. Animals had free access tofood and water throughout the experiment. Representative results aregiven in the Table. Results for Desmopressin are given for comparison. %inhibition of urine output Compound of Example Dose (at 1 hour) 1 1mg/kg 82 14 1 mg/kg 84 52 1 mg/kg 90 54 1 mg/kg 68 85 1 mg/kg 63 90 1mg/kg 60 101 1 mg/kg 74 104 1 mg/kg 81 109 1 mg/kg 73 110 1 mg/kg 80 1121 mg/kg 75 114 1 mg/kg 85 115 1 mg/kg 88 0.1 mg/kg 37 Desmopressin 1mg/kg 100 10 mg/kg 100

EXAMPLE 119 Pharmaceutical Composition for Tablet

[0117] Tablets containing 100 mg of the compound of Example 1 as theactive agent are prepared from the following: Compound of Example 1200.0 g Corn starch 71.0 g Hydroxypropylcellulose 18.0 gCarboxymethylcellulose calcium 13.0 g Magnesium stearate 3.0 g Lactose195.0 g Total 500.0 g

[0118] The materials are blended and then pressed to give 2000 tabletsof 250 mg, each containing 100 mg of the compound of Example 5.

[0119] The foregoing Examples demonstrate that compounds within thescope of the invention are readily prepared using standard chemicaltechniques, and that these compounds have the biological properties thatwould be expected of V₂ receptor agonists. In particular, the compoundsare potent antidiuretics in an animal model of vasopressin deficiency.Thus it is clear that they may be useful in the treatment of humandiseases that are currently treatable with Desmopressin, such as centraldiabetes insipidus, nocturnal enuresis and nocturia. It has further beensuggested that antidiuretics such as Desmopressin may be useful incertain types of urinary incontinence. These arguments would also extendto the compounds of the present invention.

[0120] Desmopressin is also used in the treatment of certain coagulationdisorders. There is good evidence to suggest that this action is alsomediated through the V₂ receptor (see for example J E Kaufmann et al.,“Vasopressin-induced von Willebrand factor secretion from endothelialcells involves V₂ receptors and cAMP”, J. Clin. Invest. 106, 107-116,2000; A Bernat et al., “V₂ receptor antagonism of DDAVP-induced releaseof hemostasis factors in conscious dogs”, J. Pharmacol. Exp. Ther. 282,597-602, 1997), and hence it would be expected that the compounds of thepresent invention should be useful pro-coagulants.

[0121] The scope of the present invention is further defined in thefollowing claims.

1. A compound according to general formula 1, or a pharmaceutically acceptable salt therefor,

wherein: A is a bicyclic or tricyclic azepine derivative selected from general formulae 2 to 7

A¹, A⁴, A⁷ and A¹⁰ are each independently selected from CH₂, O and NR⁸; A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ are each independently selected from CH and N; either A⁵ is a covalent bond and A⁶ is S, or A⁵ is N═CH and A⁶ is a covalent bond; A⁸ and A¹² are each independently selected from NH and S; A¹⁶ and A¹⁷ are both CH₂, or one of A¹⁶ and A¹⁷ is CH₂ and the other is selected from CH(OH), CF₂, O, SO_(x), and NR⁸, V¹ and V² are both H, OMe or F, or one of V¹ and V² is OH, OMe, OBn, OPh, O-acyl, Br, Cl, F, N₃, NH₂, NHBn or NH-acyl and the other is H, or V¹ and V² together are ═O, —S(CH₂)_(p)S— or —O(CH₂)_(p)O—; W¹ is either O or S; X¹ and X² are both H, or together are ═O or ═S; Y is OR⁵ or NR⁶R⁷; Z is S or —CH═CH—; R¹, R², R³ and R⁴ are independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br; R⁵ is selected from H and lower alkyl; R⁶ and R⁷ are independently selected from H and lower alkyl, or together are —(CH₂)_(n)—; R⁸ is H or lower alkyl; n=3, 4, 5 or 6; p=2 or 3; and x is 0, 1 or
 2. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 2. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 3. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 4. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 5. 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 6. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula
 7. 8. A compound according to claim 1 or claim 7, or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 7, Z is —CH═CH— and both A¹⁶ and A¹⁷ are —CH₂—.
 9. A compound according to any of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein one of R¹ and R² is Cl or Me and the other is H, and both R³ and R⁴ are H.
 10. A compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein one of V¹ and V² is OMe or OBn and the other is H.
 11. A compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X¹ and X² together are ═O and Y is NR⁶R⁷.
 12. A compound according to any of claims 1 or 7 to 11, or a pharmaceutically acceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl and the other is H; R^(c) is methyl or benzyl; R⁶ and R⁷ are independently selected from H and lower alkyl, or together are —(CH₂)_(n)—; and n is 3, 4, 5 or
 6. 13. A compound according to any of claims 1 or 7 to 12, or a pharmaceutically acceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl and the other is H; R^(c) is methyl or benzyl; and R⁶ and R⁷ are independently selected from H and lower alkyl, or together are —(CH₂)_(n)—; and n is 3,4, 5 or
 6. 14. A compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein V¹ and V² are both H.
 15. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein X¹ and X² together are ═O and Y is NR⁶R⁷.
 16. A compound according to any of claims 1 or 7 to 9 or 14 or 15, or a pharmaceutically acceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl and the other is H; R⁶ and R⁷ are independently selected from H and lower alkyl, or together are —(CH₂)_(n)—; and n is 3,4, 5 or
 6. 17. A compound according to any of claims 1 or 7 to 9 or 14 to 16, or a pharmaceutically acceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl and the other is H; R⁶ and R⁷ are independently selected from H and lower alkyl, or together are —(CH₂)_(n)—; and n is 3, 4, 5 or
 6. 18. A compound according to any preceding Claim which is selected from 1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide, (4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, (4R)-1-(3-chloro-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide, (4R)-1-(2-chloro-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide, (4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, (4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, (4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, (4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzyl-carbamoyl)4methoxy-L-proline-N,N-dimethylamide, (4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-yl carbonyl)2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide, (4R)-1-(2-chloro-4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-benzylcarbamoyl)-4methoxy-L-proline-N,N-dimethylamide, and (4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylthioamide or a pharmaceutically acceptable salt thereof.
 19. A use for a compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, which is as a component of a pharmaceutical composition.
 20. A use for a compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, which is as a therapeutic agent for the treatment of nocturnal enuresis, nocturia, polyuria resulting from central diabetes insipidus, urinary incontinence and bleeding disorders.
 21. A pharmaceutical composition which contains active agent selected from compounds and pharmaceutically acceptable salts according to any of claims 1 to
 18. 22. A pharmaceutical composition according to claim 21, which composition is for the treatment of polyuria.
 23. A pharmaceutical composition according to claim 21, which composition is for the control of urinary incontinence.
 24. A pharmaceutical composition according to claim 21, which composition is for voiding postponement.
 25. A pharmaceutical composition according to claim 21, which composition is for the treatment of bleeding disorders.
 26. A method of treatment of nocturnal enuresis, nocturia and central diabetes insipidus, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to claim
 21. 27. A method for the control of urinary incontinence, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to claim
 21. 28. A method of treatment according to claim 27, wherein the treatment results in voiding postponement
 29. A method of treatment of bleeding disorders, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to claim
 21. 